We have improved the aerodynamic properties of pyrazinamide loaded large porous particles (PZA-LPPs) designed for pulmonary delivery. To overcome the segregation of the different components occurring during the spray drying process and to obtain homogeneous LPPs, spray drying parameters were modified to decrease the drying speed. As a result, good aerodynamic properties for lung delivery were obtained with a fine particle fraction (FPF) of 40.1±1.0%, an alveolar fraction (AF) of 29.6±3.1%, a mass median aerodynamic diameter (MMADaer) of 4.1±0.2μm and a geometric standard deviation (GSD) of 2.16±0.16. Plasma and epithelial lining fluid (ELF) concentrations of pyrazinamide were evaluated after intratracheal insufflation of PZA-LPPs (4.22mgkg(-1)) into rats and compared to intravenous administration (iv) of a pyrazinamide solution (5.82mgkg(-1)). The in vivo pharmacokinetic evaluation of PZA-LPPs in rats reveals that intratracheal insufflation of PZA-LPPs leads to a rapid absorption in plasma with an absolute bioavailability of 66%. This proves that PZA-LPPs dissolve fast upon deposition and that PZA crosses efficiently the lung barrier to reach the systemic circulation. PZA concentrations were 1.28-fold higher in ELF after intratracheal administration than after iv administration and the ratio of ELF concentrations over plasma concentrations was 2-fold greater. Although these improvements are moderate, lung delivery of PZA appears an interesting alternative to oral delivery of the molecule and should now be tested in an infected animal model to evaluate its efficacy against Mycobacterium tuberculosis.
Keywords: Aerodynamic properties; Lung delivery; Pharmacokinetics; Pyrazinamide; Tuberculosis.
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